Der Effekt parasympathischer Stimulation auf die Entstehung von Arrhythmien beim langen QT-Syndrom Typ 3

Eine parasympathische Stimulation beim LQTS 3 scheint pathophysiologisch das Auftreten einer Bradykardie und das Auftreten von Arrhythmien vom Typ der Torsade de Pointes zu begünstigen. Dieses wurde am Model der genetisch veränderten ∆KPQ SCN5A Knock-in Maus untersucht. Bei frei laufenden ∆KPQ SCN5A Tieren traten unter Carbachol (0,5 mg/kg KG) Bradykardien und nachfolgende Bigemini und TdP (p<0,05 vs. Baseline und vs. WT) auf. Unter Atropin (0,5 mg/ kg KG) traten keine Arrhythmien auf. Am isolierten ∆KPQ SCN5A Herz konnte gezeigt werden, dass unter Carbachol primär keine Verlängerung der APD auftritt. Es kommt aber zu Bradykardien und in Folge dieser treten frequenzbedingt Verlängerungen der APD auf (p< 0,05). Parasympathische Stimulation provoziert beim LQTS 3 Arrhythmien. Wesentlich dafür ist der bradykardisierende Effekt der parasympathischen Stimulation. Eine parasympatholytische Medikation könnte helfen, TdP in Notfallsituationen beim Patienten mit dem LQTS 3 zu beenden

Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3

AIMS: Clinical observations in patients with long QT syndrome carrying sodium channel mutations (LQT3) suggest that bradycardia caused by parasympathetic stimulation may provoke torsades de pointes (TdP). beta-Adrenoceptor blockers appear less effective in LQT3 than in other forms of the disease. METHODS AND RESULTS: We studied effects of autonomic modulation on arrhythmias in vivo and in vitro and quantified sympathetic innervation by autoradiography in heterozygous mice with a knock-in deletion (DeltaKPQ) in the Scn5a gene coding for the cardiac sodium channel and increased late sodium current (LQT3 mice). Cholinergic stimulation by carbachol provoked bigemini and TdP in freely roaming LQT3 mice. No arrhythmias were provoked by physical stress, mental stress, isoproterenol, or atropine. In isolated, beating hearts, carbachol did not prolong action potentials per se, but caused bradycardia and rate-dependent action potential prolongation. The muscarinic inhibitor AFDX116 prevented effects of carbachol on heart rate and arrhythmias. beta-Adrenoceptor stimulation suppressed arrhythmias, shortened rate-corrected action potential duration, increased rate, and minimized difference in late sodium current between genotypes. beta-Adrenoceptor density was reduced in LQT3 hearts. Acute beta-adrenoceptor blockade by esmolol, propranolol or chronic propranolol in vivo did not suppress arrhythmias. Chronic flecainide pre-treatment prevented arrhythmias (all P < 0.05). CONCLUSION: Cholinergic stimulation provokes arrhythmias in this model of LQT3 by triggering bradycardia. beta-Adrenoceptor density is reduced, and beta-adrenoceptor blockade does not prevent arrhythmias. Sodium channel blockade and beta-adrenoceptor stimulation suppress arrhythmias by shortening repolarization and minimizing difference in late sodium current.status: publishe

Knock-in gain-of-function sodium channel mutation prolongs atrial action potentials and alters atrial vulnerability

BACKGROUND Patients with long QT syndrome (LQTS) are at increased risk not only for ventricular arrhythmias but also for atrial pathology including atrial fibrillation (AF). Some patients with "lone" AF carry Na(+)-channel mutations. OBJECTIVE The purpose of this study was to determine the mechanisms underlying atrial pathology in LQTS. METHODS In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na(+) channel (Delta KPQ-SCN5A) and wild-type (WT) littermates, atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed. RESULTS Atrial action potential duration, effective refractory period, cycle length, and PQ interval were prolonged in Delta KPQ-SCN5A hearts (all P &lt;.05). Flecainide (1 mu M) reversed atrial action potential duration prolongation and induced postrepolarization refractoriness (P &lt;.05). Arrhythmias were infrequent during regular rapid atrial rate in both WT and Delta KPQ-SCN5A but were inducible in 15 (38%) of 40 Delta KPQ-SCN5A and 8 (29%) of 28 WT mice upon extrastimulation. Pacing protocols generating rapid alterations in rate provoked atrial extrasystoles and arrhythmias in 6 66%) of 9 Delta KPQ-SCN5A but in 0 (0%) of 6 WT mice (P &lt;.05). Atrial diameter was increased by nearly 10% in Delta KPQ-SCN5A mice &gt; 5 months old without increase in fibrotic tissue. CONCLUSION Murine hearts bearing an LQT3 mutation show abnormalities in atrial electrophysiology and subtle changes in atrial dimension, including an atrial arrhythmogenic phenotype on provocation. These results support clinical data suggesting that LQTS mutations can cause atrial pathology and arrhythmogenesis and indicate that murine sodium channel LQTS models may be useful for exploring underlying mechanisms